Basic Research

Basic research

Mood disorder and epilepsy: a neurobiologic perspective of their relationship Andres M. Kanner, MD

ood disorders are the most frequent psychiatric M 1 comorbidity in patients with epilepsy. For example, in a population-based study carried out in Canada, Tellez- Zenteno et al found a 17.4% lifetime prevalence of major depressive disorders in these patients (95%CI: 10.0-24.9) compared with 10.7% (95%CI: 10.2-11.2) in the general population.2 Furthermore, patients with epilepsy had a 24.4% (95%CI: 16.0-32.8) lifetime prevalence for any type of mood disorder vs 13.2% (95%CI: 12.7-13.7) among the general population. In addition, the lifetime prevalence of suicidal ideation was twice as high in patients with epilepsy (25%; 95%CI: 17.4-32.5) compared with that of the general population (13.3%; 95%CI 12.8- 13.8). Among the different types of epilepsy, temporal lobe epilepsy (TLE) and frontal lobe epilepsy (FLE) have been associated most frequently with the occurrence of mood disorders.1 The high association between

Mood disorders are the most frequent psychiatric comorbidity in epilepsy, and in particular in temporal lobe epilepsy. For a long time, depressive disorders were considered to be the expression of a reactive process to the obstacles of a life with epilepsy. Data obtained in the last two decades, however, have demonstrated biochemical, neuropatholog- ical, and neurophysiologic changes mediating the development of mood disorders, which in fact can be tested in animal models. Furthermore, there is also evidence that mood disorders and epilepsy have a complex relationship which is bidirectional; that is, not only are patients with epilepsy at greater risk of developing depression, but patients with depression have a higher risk of developing epilepsy. Such a relationship can only be explained by the existence of common pathogenic mechanisms that are operant in both conditions. These include changes in neurotransmitters, such as serotonin, norepinephrine, glutamate, and Ͳ-aminobutyric acid. Such a bidirectional relationship also appears to have important clinical consequences. Indeed, patients with a history of mood disorders are twice as likely to develop pharmacoresistant epilepsy as those without such a history. These data are reviewed in this article. © 2008, LLS SAS Dialogues Clin Neurosci. 2008;10:39-45.

Keywords: serotonin; norepinephrine; hippocampal atrophy; major depressive Address for correspondence: Andres M. Kanner, MD, Rush Epilepsy Center, Rush disorder; genetically epilepsy-prone rat University Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA (e-mail: [email protected]) Author affiliations: Professor of Neurological Sciences and Psychiatry, Rush Medical College; Director, Laboratory of Electroencephalography and Video- EEG-Telemetry; Associate Director, Section of Epilepsy and Rush Epilepsy Center, Rush University Medical Center, Chicago, Illinois, USA

Selected abbreviations and acronyms Neurotransmitter changes in animal models of 5-HT serotonin epilepsy: what do they have in common with mood DA dopamine disorders? GABA Ͳ-aminobutyric acid GEPR genetic epilepsy-prone rat The pathogenic role played by neurotransmitters such as NE norepinephrine serotonin (5-HT), norepinephrine (NE), and dopamine TLE temporal lobe epilepsy (DA) in the pathophysiology of mood disorders has been recognized for four decades.4 More recently, however, γ- TLE and FLE on the one hand and mood disorders on aminobutyric acid (GABA) and glutamate have been the other is not surprising, given the evidence that these identified as having a significant pathogenic role as well. conditions may share common pathogenic mechanisms. The pivotal pathogenic role of GABA and glutamate in The purpose of this article is to review such evidence. epilepsy has been demonstrated in multiple experimental studies with animals and humans. The role of 5-HT Animal models and NE is less recognized, but well substantiated in animal and human studies. This section will focus on the How does epileptic activity facilitate the development common pathogenic mechanisms mediated by NE and of symptoms of depression? 5-HT in mood disorders and epilepsy. The genetic epilepsy-prone rat (GEPR) with its two In a recent study, Mazarati et al investigated whether strains (GEPR-3 and GEPR-9) provides an animal chronic increase in seizure susceptibility induced by kin- model of both epilepsy and depression.5 Both strains are dling results in the development of behavior suggestive characterized by genetically determined predisposition of “symptoms of depression” in rats.3 To that end, 3-week- to sound-induced generalized tonic/clonic seizures old Wistar rats underwent a rapid kindling with 84 sub- (GTCS) as well as marked kindling acceleration, with the convulsant electrical stimulations to the ventral hip- most rapid rate exhibited by GEPR-9.5,6 In addition, pocampus every 5 minutes. Two to 4 weeks later, the GEPRs display similar endocrine abnormalities to those investigators subjected the rats to two tests, the forced identified in patients with major depressive disorder, such swim test (FST) and the test of taste preference for calo- as increased corticosterone serum levels, deficient secre- rie-free saccharin or sucrose solutions. These tests are tion of growth hormone, and hypothyroidism.5 widely used in the investigation of the equivalent symp- Both strains of rats have innate noradrenergic and sero- toms of depression in animal models. In the FST, the rat tonergic pre and postsynaptic transmission deficits. Of is placed in a situation of despair, which allows for the note, GEPR-9 rats have a more pronounced NE trans- assessment of its ability to adopt active strategies in an mission deficit and, in turn, exhibit more severe seizures inescapable stressful situation. Failure to do so, as evi- than GEPR-3 rats.5 Deficient arborization of neurons denced by increased immobility time during the FST, is arising from the locus coeruleus, coupled with excessive interpreted as being equivalent to a depression-like state. presynaptic suppression of stimulated NE release in the The second test tries to replicate the loss of the animal’s terminal fields and lack of postsynaptic compensatory ability to experience pleasure. In rats, such symptoms can upregulation, mediate the noradrenergic deficiencies.5-8 be assessed by the loss of taste preference; although nor- There is also evidence of deficits in serotonergic arboriza- mal animals prefer sweetened to regular water, animals tion in the GEPR’s brain coupled with deficient postsy- with suspected depression do not exhibit such a prefer- naptic serotonin1A (5-HT1A)receptor density in the hip- ence. pocampus.5,9-11 Increments of either NE and/or 5-HT Mazarati et al found that kindled animals exhibited a sus- transmission can prevent seizure occurrence, while reduc- tained increase in immobility time in the FST and the tion will have the opposite effect.5 Thus, the selective loss of taste preference toward calorie-free saccharin, as serotonin reuptake inhibitor (SSRI) sertraline resulted compared with controls. They concluded that that “the in a dose-dependent seizure-frequency reduction in the neuronal plastic changes associated with the kindling GEPR which correlates with the extracellular thalamic state are accompanied by the development of depressive serotonergic thalamic concentration.10,11In addition, the behavior.” 5-HT precursor 5-HTP has been shown to have anticon-

40 Mood disorder and epilepsy - Kanner Dialogues in Clinical Neuroscience - Vol 10 . No. 1 . 2008

vulsant effects in GEPRs when combined with a sant effect of VNS against electroshock or pentylenete- monoamine-oxidase inhibitor (MAOI), while SSRIs and trazol-induced seizures.23 Of note, deletion of NE neurons MAOIs have been found to exert anticonvulsant effects resulted in a significant immobility time in the FST. in genetically prone epilepsy mice and baboons, as well as in non-genetically-prone cats, rabbits, and rhesus mon- Human studies keys.12-15

The antiepileptic effect mediated at the 5-HT1A recep- An abnormal serotonergic transmission has been found tors has been related to a membrane hyperpolarizing in the brain of depressed patients through the measure- 24-27 response associated with increased potassium conduc- ment of 5-HT1A receptors. Using positron-emission tance in hippocampal kindled seizures in cats, and in tomography (PET) imaging, a decrease in intrahippocampal kainic acid-induced seizures in freely 5-HT1A receptor binding has been also identified in moving rats.16 In fact, antiepileptic drugs (AEDs) with patients with TLE.28-30 Deficits in 5-HT transmission in established psychotropic effects such as carbamazepine, human depression is thought to be partially related to a valproic acid, and lamotrigine have been found to cause paucity of serotonergic innervation of its terminal areas an increase in 5-HT.17 Furthermore, the anticonvulsant suggested by a scarcity of 5-HT levels in brain tissue, protection of carbamazepine can be blocked with 5-HT- plasma, and platelets, and with a deficit in serotonin depleting drugs in GEPRs.18 transporter binding sites in postmortem human brain.31-35 An anticonvulsant effect of serotonergic activity has been Serotonin stores and transporter protein are important reported in other animal models of epilepsy. Lopez components of serotonin terminals, so that a combined

Meraz et al studied the impact of two 5-HT1A receptor deficit is a plausible indicator of reduced axonal branch- agonists, 8-OH-DPAT and indorenate, in three animal ing and synapse formation. models of epileptic seizures (clonic-tonic induced by With respect to abnormal serotonergic activity in func- pentylenetetrazol (PTZ), status epilepticus of limbic tional neuroimaging studies of patients with primary seizures induced by kainic acid (KA) and tonic-clonic major depression, Sargent et al demonstrated reduced 5- 19 seizures induced by amygdala kindling) in Wistar rats. HT1A receptor binding potential of values in frontal, tem- 8-OH-DPAT lowered the incidence of seizures and the poral, and limbic cortex with PET studies using mortality induced by PTZ, increased the latency and [11C]WAY-100635 in both unmedicated and medicated reduced the frequency of wet-dog shake and generalized depressed patients compared with healthy volunteers.24 seizures induced by KA, and at high doses diminished Of note, binding potential values in medicated patients the occurrence and delayed the establishment of status were similar to those in unmedicated patients. Drevets et epilepticus. Indorenate increased the latency to the PTZ- al, using the same radioligand, reported a decreased bind- induced seizures and decreased the percentage of rats ing potential of 5-HT1A receptors in mesial-temporal cor- that showed tonic extension and death, augmented the tex and in the raphe in 12 patients with familial recurrent latency to wet-dog shake and generalized seizures, and major depressive episodes, compared with controls.25 A diminished the number of generalized seizures. deficit in the density or affinity of postsynaptic 5-HT1A Clinckers et al investigated the impact of oxcarbazepine receptors has been identified in the hippocampus and (OXC) infusion on the extracellular hippocampal con- amygdala of untreated depressed patients who commit- centration of 5-HT and DA in the focal pilocarpine ted suicide.26 In addition, impaired serotonergic trans- model for limbic seizures.20 When OXC was administered mission has been associated with defects in the dorsal together with verapamil or probenecid (so as to ensure raphe nuclei of suicide victims with major depressive dis- its passage through the blood-brain barrier), complete order, consisting of an excessive density of serotonergic seizure remission was obtained, associated with an somatodendritic impulse-suppressing 5-HT1A autore- increase in 5-HT and DA extracellular concentrations.21 ceptors.27

In addition, it has been suggested that the anticonvulsant Similar abnormalities in 5-HT1A receptor binding have effect of vagus nerve stimulation (VNS) in the rat could been identified in patients with TLE. For example, in a PET 22 be mediated by activation of the locus coeruleus. study of patients with TLE using the 5-HT1A receptor Deletion of noradrenergic and serotonergic neurons in antagonist ([18F] trans-4-fluro-N-2-[4-(2-methoxyphenyl) the rat prevents or reduces significantly the anticonvul- piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexanecarboxam-

41 Basic research

ide), reduced 5-HT1A binding was found in mesial tempo- with the magnitude of hippocampal abnormalities iden- ral structures ipsilateral to the seizure focus, in patients with tified with 1H magnetic resonance spectroscopic imaging and without hippocampal atrophy.28 In addition, a 20% (1H-MRSI) technique at 4.1 Tesla using creatine/N-acety- binding reduction was found in the raphe and a 34% lower laspartate ratio maps.39 binding in the ipsilateral thalamic region to the seizure focus. In a separate PET study aimed at quantifying 5- Clinical implications

HT1A receptor binding in 14 patients with TLE, decreased binding was identified in the epileptogenic hippocampus, The existence of common pathogenic mechanisms amygdala, anterior cingulate, and lateral temporal neocor- between mood disorders and epilepsy may explain the tex ipsilateral to the seizure focus, as well as in the con- higher incidence of mood disorders in patients with tralateral hippocampi, but to a lesser degree, and in the epilepsy. In theory, however, patients with mood disorders raphe nuclei.29 should be at greater risk of suffering from epilepsy fol-

Other investigators using the 5-HT1A tracer, 4,2- lowing the development of the depressive disorder. Data (methoxyphenyl)-1-α[2-(N-2-pyridinyl)-p-fluorobenza- from three population-based studies appear to confirm this mido]ethylpiperazine ([18F]MPPF), found that the hypothesis. Indeed, while, depression in patients with decrease in binding of 5-HT1A was significantly greater epilepsy is typically conceptualized as a “complication” of in the areas of seizure onset and propagation identified the seizure disorder, such a “unidirectional relationship” with intracranial electrode recordings. As in the other between the two disorders was called into question in the studies, reduction in 5-HT1A binding was present, even last 15 years, first in a Swedish population-based-case con- when quantitative and qualitative MRI were normal.30 trol study in which depression was found to be seven times

Reduction in 5-HT1A receptor binding is not restricted more common among patients with new-onset epilepsy, to patients with TLE. PET studies with the 5-HT1A preceding the seizure disorder, than among age- and sex- receptor antagonist carbonyl-carbon 11-WAY-100635 matched controls.40 When analyses were restricted to cases ([11c]WAY-100635) found a decreased binding potential with a “localized-onset” seizure, depression was 17 times in the dorsolateral prefrontal cortex, raphe nuclei, and more common among cases than among controls. Next, in hippocampus of 11 patients with juvenile myoclonic a population-based study that included all adults aged 55 epilepsy compared with 11 controls.36 years and older at the time of the onset of their epilepsy, In a recently published study, Hasler et al compared living in Olmstead County, Minnesota (USA),41 the inves-

5-HT1A receptor binding between 37 TLE patients with tigators found that a diagnosis of depression preceding the and without major depressive disorder (MDD) with inter- time of their first seizure was 3.7 times more frequent 37 ictal PET using the 5-HT1A antagonist [(18)F]FCWAY. among cases than among controls after adjusting for med- The MDD was diagnosed by clinical and structured psy- ical therapies for depression.As in the Swedish study,40 this chiatric interviews. They found that, in addition to a increased risk was greater among cases with partial-onset decrease in 5-HT1A receptor binding in the epileptic focus, seizures. An interesting finding of this study was that, patients with TLE and MDD exhibited a significantly among people with epileptic seizures, an episode of major more pronounced reduction in 5-HT1A receptor binding, depression had taken place closer to the time of the first extending into nonlesional limbic brain areas outside the seizure than for controls.Another population-based study epileptic focus.The side of the ictal focus and the presence carried out in Iceland investigated the role of specific of mesial temporal sclerosis were not associated with the symptoms of depression in predicting the development of presence of comorbid depression. In a second study in 45 unprovoked seizures or epilepsy in 324 children and adults, patients with TLE, Theodore et al demonstrated an aged 10 years and older with a first unprovoked seizure or inverse correlation between increased severity of symp- newly diagnosed epilepsy and 647 controls.42 Major depres- toms of depression identified on the Beck Depression sion was associated with a 1.7-fold increased risk for devel-

Inventory and 5-HT1A receptor binding at the ipsilateral oping epilepsy while a history of attempted suicide was 5.1- hippocampus to the seizure focus and to a lesser degree at fold more common among cases than among controls. the contralateral hippocampus and midbrain raphe.38 Jones et al studied the cognitive and psychiatric profile Likewise, Gilliam et al correlated the severity of symptoms of 103 children aged 8 to 18 years, 53 with recent onset of depression using the BDI-II in 31 patients with TLE epilepsy (<1 year in duration) of idiopathic etiology and

42 Mood disorder and epilepsy - Kanner Dialogues in Clinical Neuroscience - Vol 10 . No. 1 . 2008

50 healthy children matched for age.43 Each child under- seizures had been controlled in 462 patients, while in 318 went a structured psychiatric diagnostic interview to patients epilepsy remained refractory to AED therapy.46 characterize the spectrum of lifetime-to-date history of Univariate and multivariate logistic regression analyses comorbid psychiatric disorder. Compared with the con- demonstrated that pharmacoresistance was associated trol group, children with epilepsy exhibited an elevated with prior or current psychiatric comorbidity, particularly rate of lifetime-to-date Diagnostic and Statistical Manual depression and intermittent recreational drug use. of Mental Disorders, 4th edition (DSM-IV)44 Axis I dis- The negative impact of psychiatric history on seizure con- orders, including significantly higher rates of depressive trol has not been restricted to pharmacotherapy, but has disorders (22.6 vs 4%), anxiety disorders (35.8 vs 22%), been identified in studies that investigated postsurgical and attention-deficit-hyperactivity disorder (ADHD, 26.4 seizure outcome following an anterotemporal lobectomy vs 10%). Of note, 45% of children with epilepsy exhib- (ATL). The first study by Anhoury et al reported that a ited DSM-IV Axis I disorders before the first recognized presurgical psychiatric history was associated with a seizure. worse postsurgical seizure outcome following an ATL in Data from another study suggested that psychiatric 126 patients.47 In a recent study, Kanner et al demon- pathology could be a risk factor for the development of strated that a lifetime history of depression was a pre- unprovoked nonfebrile seizures and epilepsy in children. dictor of failure to reach a postsurgical seizure outcome For example, McAfee et al conducted a retrospective free of auras and disabling seizures following an ATL in cohort study in 133 440 pediatric patients (age 6 to 17 100 consecutive patients followed for a mean period of years) without history of seizures or prior use of anti- 8.3±3.3 years.48 (Kanner et al, unpublished material). convulsant medications.45 The data source for this study was a research database containing pharmacy and med- Conclusion ical claims for members of a large US-based managed care organization. The incidence rate of seizures among The data presented in this article are clearly indicative of children without psychiatric diagnoses was 149 per 100 a complex relationship between mood disorders and 000 person-years (95% CI 122-180), while that among epilepsy, which is based on the sharing of common path- children with psychiatric diagnoses other than ADHD ogenic mechanisms.This review was restricted to the role was 513 per 100 000 person-years (95% CI 273-878). of NE and 5-HT.Yet, the potential pathogenic mechanisms include DA, GABA, and glutamate, as well as The impact of a history of depression abnormalities of common neuroanatomical structures preceding the onset of epilepsy that are part of the limbic circuit, including amygdala, on the course of the seizure disorder hippocampus, orbitofrontal and mesial frontal cortex, nucleus accumbens, basal ganglia and thalamic nuclei, The existence of common pathogenic mechanisms and the raphe nuclei and locus coeruleus.49 The implica- appears to have an impact on the response to treatment tions for neurologists are not merely theoretical, but bear of epileptic seizures. For example, in a study in 780 great significance with respect to the negative impact of patients with newly diagnosed epilepsy that were fol- mood disorders on the response to pharmacologic and lowed over a 20-year period, Hitiris et al found that surgical treatments of seizures. ❏

REFERENCES 5. Jobe PC, Weber RH. Affective disorder and epilepsy comorbidity in the genetically epilepsy prone-rat (GEPR). In: Gilliam FG, Kanner AM, Sheline YI, eds. Depression and Brain Dysfunction. London, UK: Taylor & Francis; 2006:121-158. 1. Kanner AM, Balabanov A. Depression in epilepsy: How closely related 6. Clough RW, Peterson BR, Steenbergen JL et al. Neurite extension of devel- are these two disorders? Neurology. 2002;58(suppl 5):S27-S39. oping noradrenergic neurons is impaired in genetically epilepsy-prone rats 2. Tellez-Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S. Psychiatric (GEPR-3s): An in vitro study on locus coeruleus. Epilepsy Res. 1998;29:135-146. comorbidity in epilepsy: a population-based analysis. Epilepsia. 2007;48:2336- 7. Ryu JR, Jobe PC, Milbrandt JC, et al. Morphological deficits in nora- 2344. drenergic neurons in GEPR-9s stem from abnormalities in both the locus 3. Mazarati A, Shin D, Auvin S, Caplan R, Sankar R. Kindling epileptoge- coeruleus and its target tissues. Exp Neurol. 1999;156:84-91. nesis in immature rats leads to persistent depressive behavior. Epilepsy Behav. 8. Yan QS, Jobe PC, Dailey JW. Thalamic deficiency in norepinephrine 2007;10:377-383. release detected via intracerebral microdialysis: a synaptic determinant of 4. Schildkraut JJ. The catecholamine hypothesis of effective disorders: a seizure predisposition in the genetically epilepsy-prone rat. Epilepsy Res. review of supporting evidence. Am J Psychiatry. 1965;122:509-522. 1993;14:229-236.

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Trastorno afectivo y epilepsia: Troubles de l’humeur et épilepsie : una perspectiva neurobiológica de su perspective neurobiologique de leur relación interaction

Le trouble de l’humeur est la comorbidité la plus fré- Los trastornos afectivos constituyen la comorbilidad quente au cours de l’épilepsie, et en particulier de más frecuente en la epilepsia, particularmente en l’épilepsie du lobe temporal. Les troubles dépressifs la epilepsia del lóbulo temporal. Por largo tiempo de l’épileptique ont pendant longtemps été consi- los trastornos depresivos fueron considerados dérés comme l’expression d’une réaction aux obs- expresión de un proceso reactivo a los obstáculos tacles rencontrés au cours de la vie. Les données de una vida con epilepsia. Sin embargo, datos obte- obtenues ces 10 dernières années ont néanmoins mis nidos en las últimas dos décadas han demostrado en évidence des changements biochimiques, neuro- cambios bioquímicos, neuropatológicos y neurofi- pathologiques et neurophysiologiques facilitant siológicos que median el desarrollo de los trastor- l’émergence des troubles de l’humeur, et pouvant en nos del ánimo, los que de hecho pueden ser pro- fait être testés sur des modèles animaux. De plus, il bados en modelos animales. También existe existe également des arguments en faveur d’une evidencia que los trastornos afectivos y la epilepsia relation complexe, bidirectionnelle, entre les troubles tienen una compleja relación que es bidireccional; de l’humeur et l’épilepsie; non seulement les patients esto significa que no sólo los pacientes con epilep- épileptiques ont plus de risque de développer une sia tienen mayor riesgo de desarrollar depresión, dépression, mais les patients dépressifs ont quant à sino que los pacientes con depresión tienen mayor eux un risque plus élevé de développer une comitia- riesgo de desarrollar epilepsia. Tal relación sólo lité. Une telle relation ne peut s’expliquer que par puede ser explicada por la existencia de mecanis- l’existence de mécanismes pathogéniques communs mos patogénicos comunes que operan en ambas intervenant dans les deux affections. Des modifica- direcciones. Estos incluyen cambios en neurotrans- tions au niveau des neurotransmetteurs, comme la misores como serotonina, noradrenalina, glutamato sérotonine, la norépinéphrine, le glutamate et y ácido gama-aminobutírico. Esta relación bidirec- l’acide Ͳ-aminobutyrique en font partie. Ces relations cional también parece tener importantes conse- bidirectionnelles entraînent des conséquences cli- cuencias clínicas. De hecho, pacientes con historia niques importantes. En effet, les patients ayant des de trastornos afectivos duplican la probabilidad de antécédents de troubles de l’humeur ont deux fois desarrollar epilepsia resistente a fármacos en rela- plus de risque de développer une épilepsie pharma- ción con aquellos que no tienen ese antecedente. corésistante que ceux qui en sont indemnes. Ces don- Estos datos son revisados en este artículo. nées sont examinées dans notre article.

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